Gilbert’s Syndrome – The Hidden Cause of Gut-Brain Issues

Signs and Symptoms of Gilbert’s Syndrome in Adults

Do you find that your bowel movements are all over the place regardless of whether you eat the same foods?

Do you suffer from constipation?

Have you ever had yellowing of skin/eyes -jaundice?

Has your gallbladder been taken out or have your parents/grandparents had gallbladder issues or had it removed?

Do you feel nauseous after eating fatty foods or generally struggle to digest fats?

Have you been diagnosed with SIBO?

Do you suffer from depression and/or anxiety?

Is your bilirubin elevated on blood tests?

People with Gilbert’s syndrome have a higher predisposition to these issues.

Elevated Bilirubin on Blood Tests

Gilbert’s Syndrome presents as elevated bilirubin on standard Biochemistry blood test results and chances are you would have been told that constantly elevated bilirubin is ‘benign’ and nothing to worry about. This is far from the truth.

Gilbert’s Syndrome is genetic and involves several SNPs (genetic polymorphism- variation) on the UGT1A1 gene/enzyme. This is usually only picked up on a gene analysis like 23andme and is something I test for in clinic when I see continuously elevated bilirubin levels on my clients’ blood test results.

Often there are other enzymes in the glucuronidation area (one of the liver’s key phase 2 detox pathways) that are not functioning 100%.

Genetic research is showing that  over 75% of those with Gilbert’s Syndrome have multiple SNPs that affect the glucuronidation pathway in the liver.

The glucuronidation enzymes are key to phase 2 detox in the liver in its job of toxin removal and in people with UGT polymorphisms, these enzymes are functioning at only 30-50% capacity.

This means that people with Gilbert’s have a much lower ability to clear out toxins from the liver.

Often people with Gilbert’s are born with jaundice that is resolved in hospital at birth with the use of light machines. Of course, there are other reasons for elevated bilirubin on bloods such as hepatitis and liver cirrhosis, that’s why confirming with a genetic test is useful.

Most of my patients who test positive for Gilbert’s Syndrome have digestive and psychological symptoms such as depression and anxiety.

Studies have shown that only about 10% of people with Gilbert’s Syndrome are asymptomatic.

The reason I have been researching Gilbert’s Syndrome is because I have the gene and the syndrome. I have had elevated bilirubin levels my entire life un-diagnosed until I tested for the gene later in life.

My anecdotal clinical experience shows that many people who have elevated Pyrroles often also have Gilbert’s Syndrome, and my theory is that this is due to the liver’s poor ability to break down haem. Bilirubin and Pyrroles are both by-products of haem breakdown in the glucuronidation pathway in the liver.

We all have bilirubin in our blood and it’s levels fluctuate and usually sit (for most people) below 15umoL.

In people with Gilbert’s Syndrome, there are chronic elevations of bilirubin >17 umoL, often over 25 or 30 umoL such as in the example below:

Continuously elevated bilirubin on Biochemistry blood test

The syndrome was first described in 1901 and affects about 10-15% of Caucasians, higher incidence in Middle Eastern heritage (up to 25% of the population) and South East Asians.

Summary of effects on the body from Gilbert’s Syndrome

• Predisposition to gallstones and gallbladder issues (more on this below).
• Slower intestinal motility and therefore predisposition to SIBO (more on this below) and bowel flora imbalances, IBS and leaky gut. Often this is expressed via symptoms like nausea, food intolerances, bloating and ‘that heavy feeling in the stomach as if food sits there like a brick for hours’, poor hunger in the morning.
• Anxiety and depression as well as mood fluctuations, panic attacks.
• Significantly reduced handling of paracetamol, aspirin and non-steroidal anti-inflammatories (NSAIDs) toxicity- the effects of these drugs on the liver of those with Gilbert’s is much greater than an average person’s and people with Gilbert’s need to exercise more caution with doses of these medications.
• Impaired handling of dopamine (our motivation and reward neurotransmitter) and estrogen. Clinically I find that when there are COMT and PEMT snps present combined with Gilbert’s, there is usually an issue with mood, anxiety, depression as well as definite estrogen dominance symptoms such as migraines, headaches, menstrual issues such as heavy bleeding/clotting and conditions such as endometriosis and fibroids as well as fibrocystic breasts and breast cancer.
• Poor stress tolerance especially in a fasted state. People with Gilbert’s should avoid long periods of fasting, during which more bilirubin is released.

Gilbert’s Syndrome – Gut Symptoms

The UGT enzymes are expressed throughout the gastrointestinal tract so issues in Gilbert’s can present as varying gut problems.

In the liver, glucuronidation is a key process in phase 2 detox, used to detoxify environmental toxins, pesticides, drugs, hormones such as estrogen and testosterone, absorb fat soluble vitamins A, D, E and K and produce melatonin.

In Gilbert’s, the enzymes (such as UGT) involved in this process are working far from optimally.

One of the functions of this liver pathway is to escort bilirubin out of the body as it is a toxic by-product of metabolism. The liver conjugates (binds) bilirubin by binding it to glucoronides. This function doesn’t work well in Gilbert’s Syndrome. Bilirubin ends up being only partially conjugated when mixing with bile and this step is easily undone. It ends up being only partly conjugated.

Beta-glucoronidase is an important enzyme in the gallbladder and large intestine that helps with this function- this enzyme is made by some gut bacteria species endogenously.

When bilirubin comes in contact with beta-glucoronidase, it becomes unconjugated again and keeps circulating. Unconjugated bilirubin is not water soluble, which means the liver is not able to excrete it, so it just gets re-absorbed by the body again and again.

When glucuronidation is not working as it should, due to the genetic glitches or other liver pathology (sometimes alcoholism or drug use), the unconjugated bilirubin builds up in the blood with toxic effects.

Elevated bilirubin impacts intestinal health negatively because it changes the behaviour of the intestine. It causes re-distribution of the tight junctions of the intestine, setting up leaky gut leading to food intolerances and parasite/bacterial overload.

Leaky gut has major implications to the functioning of the gut as well as predisposing to autoimmunity.

Problems often manifest in the stomach- significantly delayed gastric emptying is very common. Studies have shown that in Gilbert’s, food stays in stomach for up to 3 hours, which is roughly double the amount of time compared to those who don’t have Gilbert’s.

This is why people with Gilbert’s Syndrome often complain about burping and general upper gastric discomfort.  At the same time, there is a tendency to have faster transit time in the intestine.

SIBO and Dysbiosis

The slower transit time often predisposes Gilbert’s people to SIBO (Small Intestine Bacterial Overgrowth) -an overgrowth of good and bad bacteria in the small intestine, where they are not meant to be or where there are not meant to be this many of them.

SIBO triggers many symptoms such as food intolerances, severe bloating and abdominal pain, often constipation but sometimes diarrhoea, reflux and even skin rashes and joint pains.

A common sign of SIBO is poor sugar and carb tolerance, so when people eat simple carbs like potato/sweet potato or fruits such as apples, they will get fairly immediate bloating/cramping/discomfort.

Nutrient deficiencies are always present with SIBO and will usually mean low levels of iron, magnesium, zinc, calcium and vitamin B12 as well as poor absorption of protein – thereby low levels of mood enhancing amino acids. SIBO can also contribute to leaky gut as the bacteria damage the intestinal lining leading to all the issues described above.

“Intestinal bacterial overgrowth occurs in several pathologic conditions and may result in increased bile salt and bilirubin deconjugation in the small intestine”( Vítek, L and C. Carey, M, “New pathophysiological concepts underlying pathogenesis of pigment gallstones”, Clin Res Hepatol Gastroenterol. 2012 April ; 36(2): 122–129)

In the colon, the microbiome can be greatly influenced in Gilbert’s, predisposing to a growth of unfavourable species, particularly Clostridia species and Bacteroides Fragilis that process excess bilirubin.

What we do know is that undigested starch in high carbohydrate diets and a high intake of refined sugars affects metabolism of intestinal microflora and prolongs intestinal transit time, leading to perfect conditions for gallstones to develop, especially for those with Gilbert’s. (Vítek, L and C. Carey, M, “New pathophysiological concepts underlying pathogenesis of pigment gallstones”, Clin Res Hepatol Gastroenterol. 2012 April ; 36(2): 122–129)

Gallbladder and Gallstones

The gallbladder is the critical organ for Gilbert’s – the main highway for bilirubin excretion. What happens in Gilbert’s is partly detoxified bilirubin gets re-toxified in the gallbladder. This can lead to the formation of gallstones.

Having constantly elevated bilirubin is a definite risk factor for gallstones and gallbladder sludge.

A study that looked at bile composition found that “The proportion of total bilirubin that was unconjugated was significantly higher in the bile from patients with stones than in bile from control patients” (Dutt M.K et al, “Unconjugated bilirubin in human bile: the nucleating factor in cholesterol cholelithiasis?’, J Clin Pathol 2003;56:596–598).

People with Gilbert’s have a higher rate of gallbladder issues such as gallbladder sludge, higher rates of ‘black stones’ (most common gallstone that affects both children and adults). Increased bilirubin reduces gallbladder motility, leading to this sludge formation:

“Increased proportions of unconjugated bilirubin in gallbladder bile may be a consequence of impaired gallbladder motility” and “Unconjugated bilirubin has been identified as a component of biliary sludge, which is believed to precede gallstones, particularly pigmented stones” (Dutt M.K et al, “Unconjugated bilirubin in human bile: the nucleating factor in cholesterol cholelithiasis?’, J Clin Pathol 2003;56:596–598).

Of course, not all Gilbert’s people have gallstones, but most will have symptoms of poor fat tolerance such as nausea and poor ability to digest fatty foods and may feel pain in diaphragm area.

Gilbert’s and the brain

Impaired bilirubin detoxification leads to impaired dopamine handling due to issues in the phase 2 pathway of the liver.

Impaired bilirubin detoxification leads to an increase in glutamate in the brain- glutamate is toxic to the neurons and damages cell lining in the brain. Disturbed mood and sleep often presents during high levels of bilirubin in Gilbert’s.

Also, because bilirubin build- up leads to increased intestinal permeability (leaky gut), the blood brain barrier function in those with Gilbert’s will likely be altered and allow for gut toxicity to be impacting the brain. This toxicity (from LPS- bacterial lipopolysaccharides) is what often leads to inflammatory conditions such as depression. Inflammation leads to nervous system stress and will always present with mood/brain issues.

This is an example of gut-brain axis at work. Fascinating how everything is connected, isn’t it!

Usually people have experienced diverse digestive symptoms that change from day to day and month to month and often these have not been diagnosed by conventional medicine. The gastrointestinal tract is the way bilirubin gets detoxified.

Clinically I find that many of my clients who suffer long term depression or anxiety often show up positive for Pyrroles and Gilbert’s syndrome.

Fasting is completely contra-indicated for Gilbert’s

No matter how many times I have tried fasting or similar food restriction strategies over the last 20 years of dietary experimentation, I have never been able to do it well, without major detrimental effects like worsening of gut issues, terrible mood and other ‘detox’ effects.

In truth, these are not detox effects, but a huge spike in bilirubin levels that is produced by the slowed gut function during fasting.

If you know you have high bilirubin levels even if you haven’t yet been diagnosed with Gilbert’s you need to avoid long periods of fasting at all cost as this will over time exacerbate gut and mental health issues.

What to do if you suspect you have Gilbert’s Syndrome

The first and most obvious is to look through your standard GP medical bloods under ‘Chemistry’ or ‘Biochemistry’ and read the Bilirubin line.

If it’s >15, you may have a problem. If you’ve had several historical readings >15 for many years, the chance that you have Gilbert’s is very high.

Steps to take:

1. Diagnosis: track bilirubin levels and do the genetic testing
2. Education- things that increase bilirubin include stress, fasting, synthetic estrogens, paracetamol, NSAIDs, recreational drugs that lead to high dopamine levels
3. Take zinc! Zinc helps with anxiety and reduces glutamate as well as binds unconjugated bilirubin in the blood. To determine the right form and dosage of zinc, see you trusted complementary health practitioner
4. Support glucuronidation: there are several supplements that can assist with liver detox function, Calcium d glucarate is one of them. Again, to ensure this is right for you, speak to your practitioner.
5. Support all phase 2 liver enzymes, in particular methylation, glutathionation and sulfation to reduce estrogen dominance. Cruciferous vegetables are great as they  induce both glucuronidation and glutathionation. For specific supplement support, speak to your practitioner. I also find liver function testing with each liver phase useful here.
6. A lot of gut work throughout the stomach, liver, gut lining, bowel to optimise digestion
7. Antioxidants to reduce oxidative stress

Keys to treatment:

The goal is to get the unconjugated bilirubin levels into ideal range and keep it there- this is a lifetime strategy due to the genetic nature of this condition.

1. Reduce transit time and gastric emptying – speed up the rate at which food moves through the digestive tract. This will reduce the re-toxification of bilirubin.
2. Increase bile flow- reduces stagnation of bile in gallbladder
3. Improve fat absorption or correct malabsorption issues
4. Acidify the colon- reduces beta-glucoronidase species (such as E-coli and clostridia).
5. Improve positive microbiota- bacteria that reduce bilirubin
6. Improve gap junctions/ reduce leaky gut
7. An inflammatory condition such as IBD, colitis, Crohn’s- more bilirubin will be made in order to reduce haem (which is protective of the gut lining). When inflammation is present it must be addressed as it is feeding into the bilirubin overload
8. Support liver glucuronidation pathways

Having to constantly address Gilbert’s in myself and my clients has meant that this is a key area of research and practice for me.

To learn how to manage your Gilbert’s symptoms long term, click HERE to book in a consult with Clinical Nutritionist Maria.

Acknowledgements: thank you to one of my mentors, Rachel Arthur ND for the research and clinical insights into Gilbert’s Syndrome which I have relied on in compiling this information.